Abstract: Hypertrophic cardiomyopathy is the most common inherited cardiovascular disease. It affects one in 500 of the population. It is the most frequent cause of sudden death in young people. Despite groundbreaking work in defining the genetic basis for the disease, leading to the description of more than 400 predominantly missense mutations in more than 8 largely sarcomeric genes, therapies remain palliative. In this application, I outline an innovative approach to the treatment of the underlying genetic defect in hypertrophic cardiomyopathy. Dominant negative 'poison peptide'transmission, together with a proof-of-principle phenotype reversal in a transgenic mouse model provide the rationale. The combination of allele specific RNA silencing and creative biological and physical approaches to cellular specificity provide the mechanism and route of delivery. Specificity provides the single greatest challenge and I outline several innovative approaches to overcoming this. Potential translation to patients is a theme weaved throughout the strategic plan. We begin with mutations identified in families from the Stanford Hypertrophic Cardiomyopathy Center, carry out basic RNA biology in an attempt to selectively silence these mutations in cell lines and move progressively through organ models then small animals to a pre-clinical large animal model. The approach we outline is not limited to hypertrophic cardiomyopathy. The ability to selectively modify a single mutated allele and deliver the therapy in vivo could revolutionize the treatment of diverse genetic diseases and finally fulfill the therapeutic promise of the human genome project. Finally, I argue that the most innovative ideas would never have been noticed without timing: with the genetic basis of the disease laid out, and many critical techniques on the verge of significant advancement, the time is right for a new approach. Public Health Relevance: This project will investigate novel techniques which take advantage of the cell's own components to turn off mutated genes. In particular, the project aims to translate these discoveries to the clinical care of patients with hypertrophic cardiomyopathy. This familial condition where the heart grows too thick is the most common cause of sudden death in young people and athletes.